New Approaches in Targeted Therapy for Medulloblastoma in Children (original) (raw)

Medulloblastoma (MB) is the most frequent malignant brain tumor in children. Treatment of MB is based on histopathological and molecular stratification, and includes surgical intervention, often with craniospinal irradiation and adjuvant chemotherapy. Unfortunately, however, this treatment leads to a high morbidity rate, and it does not cure all patients either, with around 30% succumbing to their disease. With improved cancer genomics and better molecular characterization, MB has been classified into four major subgroups, wingless-activated, sonic hedgehog-activated, Group 3, and Group 4, with each group consisting of additional subtypes. Recently disclosed genetic drivers of MB may in the future help improve treatment, and in this way reduce therapy-related toxicity. In this review, we describe the heterogeneity of the MB subgroups, and potential new options for targeted therapy. Medulloblastoma (MB), the most frequently occurring malignant brain tumor in children, is treated depending on histopathological and molecular stratification, and age, with the current standard of care often including surgery, craniospinal irradiation (CSI) and adjuvant chemotherapy (1). This leads to considerable morbidity among the 70% of patients that are cured, and leaves the remaining 30% in need of better therapeutic options since they are not cured (1-3). With advanced cancer genomics, elucidation of the molecular complexity of MB has resulted in its classification into four major subgroups, wingless-activated (WNT), sonic hedgehogactivated (SHH), Group 3, and Group 4 MB, with each comprising additional subtypes (2). Genomic data have also identified genetic drivers for MB, and, as specific targets, these could potentially help improve present treatment options considerably and thereby reduce therapy-related toxicity (3). In this review, we describe the heterogeneity of the MB subgroups, and some advances in targeted therapy. We also focus on pathways that drive MB tumorigenesis, and present an overview of some current preclinical and clinical studies targeting the hedgehog (HH), phosphoinositide 3-kinase (PI3K), cyclin-dependent kinase 4 and 6 (CDK4/6) pathways, as well as approaches in immunotherapy. While research continuously sheds more light on the individual genomic complexity of MB, the challenge lies in the comprehensive evaluation and translation of newly obtained data into new therapeutic approaches. Epidemiology and Symptomatology Brain tumors are the most frequent solid tumors in children, and among these, MB represents the most common malignant one, accounting for 20% of all pediatric brain tumors (1, 4). The incidence of MB in children is roughly five cases per million individuals, and in adults, around one case per 2 million individuals (4, 5). MB is mainly observed the first 9 years of life, with a peak incidence between 4 to 7 years of age (6). Although the sex predominance differs between MB subtypes, males are generally 1.5-2 times more frequently affected than females (4). The World Health Organization has classified MB as a grade IV tumor, usually originating in the cerebellum or the posterior fossa, and shown to spread via the cerebrospinal fluid to the brain and spine (2, 7). In children, MB is mostly located in the midline of the cerebellum, whereas in adults, lateral tumors are more frequent (7). Histologically, the tumor consists of densely packed cells, which are predominantly undifferentiated. If 1715 This article is freely accessible online.